1. Field of the Invention
The present invention relates to a process for purifying Iopamidol and, more particularly, to a process for purifying Iopamidol using butanol as solvent.
2. Discussion of the Background
Iopamidol is the International non-proprietary Name (INN) for L-5-.alpha.-hydroxypropionylamino-2,4,6-triiodoisophthalic acid bis-(1,3-dihydroxyisopropylamide). This compound was first described by the Swiss company Savac A.G. in the British patent no. 1,472,050. Iopamidol is used in diagnostics as non-ionic contrast medium.
Iopamidol is a white high-melting solid. Conventional syntheses of Iopamidol involve a final purification of the product in an aqueous solution. Thereafter, in order to obtain the product in solid form, it is necessary to crystallize it.
British patent No. 1,472,050 describes that Iopamidol can be isolated by evaporation of the aqueous solution followed by crystallization of the crude product obtained from ethanol. WO 88/09328 to Bracco Industria Chimica S.p.A. describes that crude Iopamidol can be obtained by evaporation of the aqueous solution followed by crystallization of the crude product from absolute ethanol. "Analytical Profiles of Drug Substances", vol. 17, pages 115-154, Academic Press, San Diego, 1988) describes that Iopamidol can be crystallized from water, with very slow kinetics, yielding a monohydrate or pentahydrate crystalline product.
Unfortunately when Iopamidol is crystallized from water or ethanol as described in the literature, a crystalline form having the required pharmaceutical properties as described in US Pharmacopoeia XXII, page 712, cannot be obtained. The product crystallized from ethanol contains an amount of ethanol corresponding to 4000-8000 ppm which cannot be removed either by heating at high temperatures or under vacuum. This product is not suitable as a pharmaceutical because its ethanol content is too high (the USA Pharmacopoeia requires that no impurity can exceed 5000 ppm). Similarly, Iopamidol crystallized from water is not suitable because in order to remove the water of crystallization, very long heating times at temperatures higher than 100.degree. C. are required. Furthermore, the yield of the crystallization from water is very poor and therefore the process is not suitable from an industrial point of view.
The literature data regarding the solubility of Iopamidol conflict with each other and therefore they do not suggest other practical solutions to solve these problems. For example, British patent no. 1,472,050 reports that Iopamidol dissolves very easily in water, has a practically unlimited solubility in methanol and has solubility in ethanol of about 10% at room temperature. However, one of the inventors of that patent, in a subsequent paper published on Boll. Chim. Farm., 120, 639, (1981), reports that Iopamidol is very soluble in water but is only slightly soluble in methanol and practically insoluble in ethanol, diethylether, benzene and chloroform. Accordingly, it is desirable to find a practical and efficient method for purifying Iopamidol.